Prof. Nathan Dascal

Professor, Department of Physiology and Pharmacology, School of Medicine, Tel Aviv University

Education

(For more information, please go to https://nathan-dascal-lab.sites.tau.ac.il/)

We are addressing key issues in molecular neurobiology and molecular cardiology: how hormones and neurotransmitters regulate the function of cardiac cells and neurons, by acting on G proteins that transmit the signal, and ion channels – proteins that underlie the electrical activity in these cells; how these functions are altered in disease; and, whenever possible, seek for treatments for the accompanying disorders. We focus on open issues in this field: protein complexes and the biochemical cascades involved in modulation of ion channels; cellular, biophysical and biochemical mechanisms that underlie the function of proteins responsible for excitability; changes in their function as a result of genetic disorders, cardiac disease and neurologic disorders. The diseases currently in focus are GNB1 Encephalopathy and epilepsy. The laboratory uses animal and cell models and a wide range of methodologies: recombinant DNA and molecular biology; protein biochemistry; kinetic/math modeling; molecular modeling; biophysics; electrophysiology; optical methods; cell culture; and other.

Main projects in the lab:

1) Molecular mechanisms of function and regulation of G protein activated K⁺ channels (GIRK). These proteins are major mediators of inhibitory effects of neurotransmitters in heart and brain. We study the regulation of these channels by receptors and G protein subunits, interactions within this protein molecule and the formation of signaling complexes with other proteins, the importance of diversity of GIRK genes in their function, their role in regulation of excitability in neurons and in disease.

2) The function of cardiac calcium channels and their regulation by auxiliary proteins, by the diversity of their isoforms (alternative splicing/posttranslational modifications), with current emphasis on fundamental and previously poorly understood aspects of adrenergic (adrenalin & noradrenalin) regulation of these channels.

3) Etiology and mechanisms of GNB1 Encephalopathy, a recently discovered neurologic disorder, caused by mutations in Gβ1 subunit of G proteins. Our studies revealed that different mutations that cause this disease, differentially and specifically affect distinct functions of the Gβ protein. In particular, they alter the regulation of GIRK channels, and affect transmitter release. Based on these findings, we currently work toward the development of treatments for GNB1-accompanying epilepsy. This work involves mouse models, human patients, and several model systems.

4) Regulation of transmitter and hormone release by neurotransmitters and G proteins (in collaboration with Prof. Ilana Lotan). Effects of G proteins and disease-causing mutations are studied in cultured secretory cells and mouse neurons.

Selected publications

(For a full list, please see https://www.ncbi.nlm.nih.gov/sites/myncbi/1NMhxNwos_5/bibliography/42050102/public/?sort=date&direction=ascending)

 Papa A, Del Rivero Morfin PJ, Chen BX, Yang L, Katchman AN, Zakharov SI, Liu G, Bohnen MS, Zheng V, Katz M, Subramaniam S, Hirsch JA, Weiss S, Dascal N, Karlin A, Pitt GS, Colecraft HM, Ben-Johny M & Marx SO. (2024) A membrane-associated phosphoswitch in Rad controls adrenergic regulation of cardiac calcium channels. J Clin Invest 134. 10.1172/JCI176943.

 Oz S, Sharon T, Surbramaniam S, Pallien T, Katz M, Tsemakhovich V, Tripathy DR, Sasson G, Chomsky-Hecht O, Vysochek L, Schulz M, Fecher-Trost C, Zuhlke K, Bertinetti D, Herberg FW, Keren-Raifman T, Flockerzi V, Hirsch JA, Klussmann E, Weiss S & Dascal N. (2023) Tripartite interactions of PKA catalytic subunit and C-terminal domains of cardiac Ca²⁺ channel modulate its β-adrenergic regulation. bioRxiv, 2023.2011.2028.564875. 10.1101/2023.11.28.564875.

 Colombo S, Reddy HP, Petri S, Williams DJ, Shalomov B, Dhindsa RS, Gelfman S, Krizay D, Rafikian EE, Bera AK, Yang M, Peng Y, Makinson CD, Boland MJ, Frankel WN, Goldstein DB & Dascal N. (2023) Epilepsy in a mouse model of GNB1 Encephalopathy arises from altered potassium channel (GIRK) signaling and is alleviated by a GIRK inhibitor. Front Cell Neurosci 17, 1175895. https://doi.org/10.3389/fncel.2023.1175895.

 Shalomov B, Handklo-Jamal R, Reddy HP, Theodor N, Bera AK & Dascal N. (2022) A revised mechanism of action of hyperaldosteronism-linked mutations in cytosolic domains of GIRK4 (KCNJ5). J Physiol London 600, 1419-1437. https://doi.org/10.1113/JP282690.

 Friesacher T, Reddy HP, Bernsteiner H, Carlo Combista J, Shalomov B, Bera AK, Zangerl-Plessl E-M, Dascal N & Stary-Weinzinger A. (2022) A selectivity filter mutation provides insights into gating regulation of a K+ channel. Comms Biol 5, 345. 10.1038/s42003-022-03303-1.

 Reddy HP, Yakubovich D, Keren-Raifman T, Tabak G, Tsemakhovich VA, Pedersen MH, Shalomov B, Colombo S, Goldstein DB, Javitch JA, Bera AK & Dascal N. (2021) Encephalopathy-causing mutations in Gβ1 (GNB1) alter regulation of neuronal GIRK channels. iScience 24, 103018. https://doi.org/10.1016/j.isci.2021.103018.

 Katz M, Subramaniam S, Chomsky-Hecht O, Tsemakhovich V, Flockerzi V, Klussmann E, Hirsch JA, Weiss S & Dascal N. (2021) Reconstitution of β-adrenergic regulation of Ca_V1.2: Rad-dependent and Rad-independent protein kinase A mechanisms. Proc Natl Acad Sci USA 118, e2100021118. 10.1073/pnas.2100021118.

 Berlin S, Artzy E, Handklo-Jamal R, Kahanovitch U, Parnas H, Dascal N & Yakubovich D. (2020) A collision coupling model governs the activation of neuronal GIRK1/2 channels by muscarinic-2 receptors. Front Pharmacol 11, 1216. 10.3389/fphar.2020.01216.

 Tabak G, Keren-Raifman T, Kahanovitch U & Dascal N. (2019) Mutual action by Gγ and Gβ for optimal activation of GIRK channels in a channel subunit-specific manner. Sci Rep 9, 508. 10.1038/s41598-018-36833-y.

 Oz S, Pankonien I, Belkacemi A, Flockerzi V, Klussmann E, Haase H & Dascal N. (2017) Protein kinase A regulates C-terminally truncated Ca_V1.2 in Xenopus oocytes: roles of N- and C-termini of the α_1C subunit. J Physiol 595, 3181-3202. 10.1113/JP274015.

 Kahanovitch U, Berlin S & Dascal N. (2017) Collision coupling in the GABA_B receptor - G protein - GIRK signaling cascade. FEBS Lett 591, 2816-2825. 10.1002/1873-3468.12756.

 Dascal N & Rubinstein M. (2017) Lithium reduces the span of G protein-activated K⁺ (GIRK) channels inhibition in hippocampal neurons. Bipolar Disord 19, 568-574. 10.1111/bdi.12536.

 Benmocha Guggenheimer A, Almagor L, Tsemakhovich V, Tripathy DR, Hirsch JA & Dascal N. (2016) Interactions between N and C termini of α_1C subunit regulate inactivation of Ca_V1.2 L-type Ca²⁺ channel. Channels (Austin) 10, 55-68. 10.1080/19336950.2015.1108499.

 Yakubovich D, Berlin S, Kahanovitch U, Rubinstein M, Farhy-Tselnicker I, Styr B, Keren-Raifman T, Dessauer CW & Dascal N. (2015) A quantitative model of the GIRK1/2 channel reveals that its basal and evoked activities are controlled by unequal stoichiometry of Gα and Gβγ. PLoS Comput Biol 11, e1004598. 10.1371/journal.pcbi.1004598.

 Weiss S & Dascal N. (2015) Molecular Aspects of Modulation of L-type Calcium Channels by Protein Kinase C. Curr Mol Pharmacol 8, 43-53. 10.2174/1874467208666150507094733.

 Dascal N & Kahanovitch U. (2015) The roles of Gβγ and Gα in gating and regulation of GIRK channels. Int Rev Neurobiol 123, 27-85. 10.1016/bs.irn.2015.06.001.

 Kahanovitch U, Tsemakhovich V, Berlin S, Rubinstein M, Styr B, Castel R, Peleg S, Tabak G, Dessauer CW, Ivanina T & Dascal N. (2014) Recruitment of Gβγ controls the basal activity of G-protein coupled inwardly rectifying potassium (GIRK) channels: crucial role of distal C terminus of GIRK1. J Physiol 592, 5373-5390. 10.1113/jphysiol.2014.283218.

 Farhy Tselnicker I, Tsemakhovich V, Rishal I, Kahanovitch U, Dessauer CW & Dascal N. (2014) Dual regulation of G proteins and the G-protein-activated K⁺ channels by lithium. Proc Natl Acad Sci U S A 111, 5018-5023. 10.1073/pnas.1316425111.

 Weiss S, Oz S, Benmocha A & Dascal N. (2013) Regulation of cardiac L-type Ca²⁺ channel Ca_V1.2 via the β-adrenergic-cAMP-protein kinase A pathway: old dogmas, advances, and new uncertainties. Circ Res 113, 617-631. 10.1161/CIRCRESAHA.113.301781.

 Oz S, Benmocha A, Sasson Y, Sachyani D, Almagor L, Lee A, Hirsch JA & Dascal N. (2013) Competitive and non-competitive regulation of calcium-dependent inactivation in Ca_V1.2 L-type Ca²⁺ channels by calmodulin and Ca²⁺-binding protein 1. J Biol Chem 288, 12680-12691. 10.1074/jbc.M113.460949.

 Edvardson S, Oz S, Abulhijaa FA, Taher FB, Shaag A, Zenvirt S, Dascal N & Elpeleg O. (2013) Early infantile epileptic encephalopathy associated with a high voltage gated calcium channelopathy. J Med Genet 50, 118-123. 10.1136/jmedgenet-2012-101223.

 Oz S, Tsemakhovich V, Christel CJ, Lee A & Dascal N. (2011) CaBP1 regulates voltage-dependent inactivation and activation of Ca_V1.2 (L-type) calcium channels. J Biol Chem 286, 13945-13953. 10.1074/jbc.M110.198424.

 Berlin S, Tsemakhovich VA, Castel R, Ivanina T, Dessauer CW, Keren-Raifman T & Dascal N. (2011) Two distinct aspects of coupling between Gαi protein and G protein-activated K⁺ channel (GIRK) revealed by fluorescently labeled Gα_i3 protein subunits. J Biol Chem 286, 33223-33235. 10.1074/jbc.M111.271056.

 Tselnicker I, Tsemakhovich VA, Dessauer CW & Dascal N. (2010) Stargazin modulates neuronal voltage-dependent Ca²⁺ channel Ca(v)2.2 by a Gβγ-dependent mechanism. J Biol Chem 285, 20462-20471. 10.1074/jbc.M110.121277.

 Berlin S, Keren-Raifman T, Castel R, Rubinstein M, Dessauer CW, Ivanina T & Dascal N. (2010) Gα_i and Gβγ jointly regulate the conformations of a Gβγ effector, the neuronal G protein-activated K⁺ channel (GIRK). J Biol Chem 285, 6179-6185. 10.1074/jbc.M109.085944.

 Rubinstein M, Peleg S, Berlin S, Brass D & Dascal N. (2007) Ga_i3 primes the G protein-activated K⁺ channels for activation by coexpressed Gbg in intact Xenopus oocytes. J Physiol 581, 17-32.

 Kanevsky N & Dascal N. (2006) Regulation of maximal open probability is a separable function of Ca_Vβ subunit in L-type Ca²⁺ channel, dependent on NH₂ terminus of α_1C (Ca_V1.2α). J Gen Physiol 128, 15-36. 10.1085/jgp.200609485.

 Ben-Chaim Y, Chanda B, Dascal N, Bezanilla F, Parnas I & Parnas H. (2006) Movement of 'gating charge' is coupled to ligand binding in a G-protein-coupled receptor. Nature 444, 106-109. 10.1038/nature05259.

 Yakubovich D, Rishal I & Dascal N. (2005) Kinetic modeling of Na⁺-induced, Gbg -dependent activation of G-protein-gated K⁺ channels. J Mol Neurosci 25, 7-20.

 Rishal I, Porozov Y, Yakubovich D, Varon D & Dascal N. (2005) Gβγ-dependent and Gβγ-independent basal activity of G protein-activated K⁺ channels. J Biol Chem 280, 16685-16694. 10.1074/jbc.M412196200.

 Ivanina T, Varon D, Peleg S, Rishal I, Porozov Y, Dessauer CW, Keren-Raifman T & Dascal N. (2004) Ga_i1 and Ga_i3 differentially interact with, and regulate, the G protein-activated K⁺ channel. J Biol Chem 279, 17260-17268.

 Ivanina T, Rishal I, Varon D, Mullner C, Frohnwieser-Steinecke B, Schreibmayer W, Dessauer CW & Dascal N. (2003) Mapping the Gβγ-binding sites in GIRK1 and GIRK2 subunits of the G protein-activated K⁺ channel. J Biol Chem 278, 29174-29183. 10.1074/jbc.M304518200.

 Ben-Chaim Y, Tour O, Dascal N, Parnas I & Parnas H. (2003) The M2 muscarinic G-protein-coupled receptor is voltage sensitive. J Biol Chem 278, 22482–22491.

 Peleg S, Varon D, Ivanina T, Dessauer CW & Dascal N. (2002) Ga_i controls the gating of the G-protein-activated K⁺ channel, GIRK. Neuron 33, 87-99.

 Dascal N. (2001) Ion-channel regulation by G proteins. Trends Endocrinol Metab 12, 391-398. 10.1016/s1043-2760(01)00475-1.

 Yakubovich D, Pastushenko V, Bitler A, Dessauer CW & Dascal N. (2000) Slow modal gating of single G protein-activated K⁺ channels expressed in Xenopus oocytes. J Physiol 524 Pt 3, 737-755. 10.1111/j.1469-7793.2000.00737.x.

 Vorobiov D, Bera AK, Keren-Raifman T, Barzilai R & Dascal N. (2000) Coupling of the muscarinic m2 receptor to G protein-activated K⁺ channels  via Ga_z and a receptor-Ga_z fusion protein. Fusion between the receptor and Ga_z eliminates catalytic (collision) coupling. J Biol Chem 275, 4166-4170.

 Ivanina T, Blumenstein Y, Shistik E, Barzilai R & Dascal N. (2000) Modulation of L-type Ca²⁺ channels by Gbg and calmodulin via interactions with N- and C-termini of a_1C. J Biol Chem 275, 39846-39854.

Dascal N. Voltage clamp recordings from Xenopus oocytes. in Current Protocols in Neuroscience (eds. Rogawski, M. & Crawley, J.) 6.12.11-16.12.12 (John Wiley & Sons, New York, 2000).

 Dascal N. (1997) Signalling via the G protein-activated K⁺ channels. Cell Signal 9, 551-573. 10.1016/s0898-6568(97)00095-8.

 Schreibmayer W, Dessauer CW, Vorobiov D, Gilman AG, Lester HA, Davidson N & Dascal N. (1996) Inhibition of an inwardly rectifying K channel by G-protein α-subunits. Nature 380, 624-627.

 Dascal N, Schreibmayer W, Lim NF, Wang W, Chavkin C, DiMagno L, Labarca C, Kieffer BL, Gaveriaux-Ruff C, Trollinger D & et al. (1993) Atrial G protein-activated K⁺ channel: expression cloning and molecular properties. Proc Natl Acad Sci U S A 90, 10235-10239. 10.1073/pnas.90.21.10235.

Dascal N & Lotan I. Expression of exogenous ion channels and neurotransmitter receptors in RNA-injected Xenopus oocytes. in Protocols in Molecular Neurobiology (eds. Longstaff, A. & Revest, P.) 205-225 (Humana Press, Totowa, NJ, 1992).

 Singer D, Biel M, Lotan I, Flockerzi V, Hofmann F & Dascal N. (1991) The roles of the subunits in the function of the calcium channel. Science 253, 1553-1557. 10.1126/science.1716787.

 Lotan I, Goelet P, Gigi A & Dascal N. (1989) Specific block of calcium channel expression by a fragment of dihydropyridine receptor cDNA. Science 243, 666-669. 10.1126/science.2464853.

 Dascal N. (1987) The use of Xenopus oocytes for the study of ion channels. CRC Crit Rev Biochem 22, 317-387. Doi 10.3109/10409238709086960.

 Dascal N, Snutch TP, Lubbert H, Davidson N & Lester HA. (1986) Expression and modulation of voltage-gated calcium channels after RNA injection in Xenopus oocytes. Science 231, 1147-1150. 10.1126/science.2418503.

 Oron Y, Dascal N, Nadler E & Lupu M. (1985) Inositol 1,4,5-trisphosphate mimics muscarinic response in Xenopus oocytes. Nature 313, 141-143. 10.1038/313141a0.

 Lotan I, Dascal N, Cohen S & Lass Y. (1982) Adenosine-induced slow ionic currents in the Xenopus oocyte. Nature 298, 572-574. 10.1038/298572a0.

We are looking for inquisitive, enthusiastic people who want to discover new principles in regulation of neuronal and cardiac function in health and disease, and engage in finding cure for specific neurological disorders. MSc/PhD students and postdocs will be considered. Starting date: October 2024